FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons

EMBO J. 2011 Jun 14;30(14):2920-33. doi: 10.1038/emboj.2011.189.


Netrin-1 induces repulsive axon guidance by binding to the mammalian Unc5 receptor family (Unc5A-Unc5D). Mouse genetic analysis of selected members of the Unc5 family, however, revealed essential functions independent of Netrin-1, suggesting the presence of other ligands. Unc5B was recently shown to bind fibronectin and leucine-rich transmembrane protein-3 (FLRT3), although the relevance of this interaction for nervous system development remained unclear. Here, we show that the related Unc5D receptor binds specifically to another FLRT protein, FLRT2. During development, FLRT2/3 ectodomains (ECDs) are shed from neurons and act as repulsive guidance molecules for axons and somata of Unc5-positive neurons. In the developing mammalian neocortex, Unc5D is expressed by neurons in the subventricular zone (SVZ), which display delayed migration to the FLRT2-expressing cortical plate (CP). Deletion of either FLRT2 or Unc5D causes a subset of SVZ-derived neurons to prematurely migrate towards the CP, whereas overexpression of Unc5D has opposite effects. Hence, the shed FLRT2 and FLRT3 ECDs represent a novel family of chemorepellents for Unc5-positive neurons and FLRT2/Unc5D signalling modulates cortical neuron migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Cell Movement
  • Cells, Cultured
  • Female
  • Gene Expression Regulation, Developmental
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Immunoblotting
  • Integrases / metabolism
  • Male
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Growth Factors / metabolism
  • Netrin Receptors
  • Netrin-1
  • Neurons / cytology
  • Neurons / metabolism*
  • Protein Binding
  • Receptors, Cell Surface / physiology*
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism


  • FLRT1 protein, mouse
  • FLRT2 protein, mouse
  • FLRT3 protein, mouse
  • Membrane Glycoproteins
  • NTN1 protein, human
  • Nerve Growth Factors
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Unc5A protein, mouse
  • Netrin-1
  • Cre recombinase
  • Integrases